High Uptake and Use of Vaginal Ring for HIV Prevention Observed in Open-Label Study

Nearly 90 percent of participants in an open-label study of a vaginal ring infused with a drug to prevent HIV are using the monthly ring at least some of the time, according to an interim analysis of study data. In addition, the rate of HIV infection among participants in the open-label study, which has no placebo arm for comparison, is half of what might be expected in the absence of the ring, according to mathematical modeling that has significant limitations.

These preliminary findings from the HIV Open Label Extension (HOPE) study were presented today during a press conference at the Conference on Retroviruses and Opportunistic Infections (CROI) in Boston and will be reported tomorrow in an oral presentation at the meeting.

"It would be ideal for women to have discreet HIV prevention tools that they want to use and can control by themselves," said Carl W. Dieffenbach, Ph.D., director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH and the primary funder of the study. "Interim data from the HOPE open-label extension study appear to be sending a positive signal about the desirability of the anti-HIV vaginal ring in a setting more like the real world than previous trials. We look forward to the final results from this study, which should provide more definitive information."

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The HOPE study launched in 2016 as a follow-on to the NIH-funded ASPIRE clinical trial. ASPIRE demonstrated that a silicone ring that continuously releases the anti-HIV drug dapivirine in the vagina safely reduced the risk of HIV infection by 27 percent. An exploratory analysis of the Phase 3 ASPIRE study data subsequently found that the monthly ring reduced the risk of HIV infection by at least 56 percent in women who used it most or all of the time. The goals of the current HOPE study are to gather data on whether and how women use the dapivirine ring knowing it is safe and moderately effective, and to further examine the relationship between adherence to the ring and protection from HIV infection. Final results are expected in 2019.

Since all HOPE study participants previously completed the ASPIRE trial without becoming HIV-infected, an aspect of their behavior other than the use of the vaginal ring may be contributing to protection from the virus, according to the study investigators. HOPE study participants received HIV prevention counseling and services during their participation in ASPIRE, which lasted for a median of one year and seven months. The women continue receiving HIV prevention counseling and services in the current study.

The Phase 3b HOPE study, also known as MTN-025, is being implemented by the NIH-funded Microbicide Trials Network (MTN) at 14 former ASPIRE study sites in Malawi, South Africa, Uganda and Zimbabwe. Because women accounted for 58 percent of new HIV infections among adults in southern and eastern Africa in 2016, protecting them from acquiring the virus is essential to controlling the HIV epidemic.

The Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, both part of NIH, co-fund the MTN with NIAID.

While ASPIRE study participants did not know until the end of the trial whether they had received the dapivirine ring or a placebo ring, the HOPE study team is offering the dapivirine ring to all who enroll. HOPE study participants are sexually active, HIV-negative women ages 20 to 49 years who participated in ASPIRE and are not pregnant. More than 1,400 women had enrolled in the HOPE study as of October 2017, the data cutoff for the interim analysis.

The HOPE study is being led by Jared Baeten, M.D., Ph.D., a professor of global health, medicine and epidemiology at the University of Washington in Seattle; Thesla Palanee-Phillips, Ph.D., M.Sc., director of network trials and research center programs at the Wits Reproductive Health and HIV Institute in Johannesburg, South Africa; and Nyaradzo M. Mgodi, M.B.Ch.B., M.Med., a clinical pathologist and clinical research site leader at the University of Zimbabwe -- University of California San Francisco Collaborative Research Program in Harare, Zimbabwe.

"Our interim analysis suggests that women in the HOPE study are choosing to use the dapivirine ring at least some of the time now that they know it can safely reduce their risk of HIV infection, and this is helping them achieve a level of protection," said Dr. Baeten.

Participants in the HOPE study are being offered the dapivirine ring to insert into their vagina for a month at a time for up to 12 consecutive months. During the first three months, the women attend monthly study visits where they may obtain a new ring. Thereafter, they attend quarterly visits where they may obtain three rings at a time, a schedule that more closely resembles how the ring might be distributed in a real-world setting.

Participants may remain in the HOPE study regardless of whether they accept or use new rings. By allowing women to opt out of ring use but remain in the study, researchers are gaining insight into whether participants like using the ring and why, as well as what factors influence use and non-use. More than 90 percent of participants accepted the ring when they entered the study.

Adherence to the ring is being assessed by measuring residual levels of dapivirine in returned rings and blood levels of dapivirine. Some 89 percent of the rings returned as of October 2017 have residual dapivirine levels consistent with some use during the prior month. In contrast, 77 percent of returned rings in the ASPIRE study had residual dapivirine levels consistent with some use during the prior month, suggesting that adherence in the HOPE study is roughly 16 percent higher than it was in ASPIRE. Investigators lacked data to precisely quantify the duration of ring use in either study. The ring is designed to be worn continuously throughout the month to provide effective protection. Measurements of blood levels of dapivirine were not included in the interim analysis.

As of October 2017, HOPE study participants have become infected with HIV at a rate of 1.9 new infections per 100 person-years of follow-up. Person-years are the sum of the number of years that each participant has been in the study.

Other forms of HIV prevention have proven to provide high levels of protection from the virus. For instance, oral tablets of the medication Truvada for HIV pre-exposure prophylaxis (PrEP) reduce the risk of HIV infection by up to 92 percent in people at high risk when taken daily as prescribed, although taking a daily pill can be challenging for some people.

Because the HOPE study lacks a concurrent control group receiving a placebo ring, investigators used a mathematical approach to estimate what the HIV incidence would be if the women in the study had lacked access to the dapivirine ring.

First, the researchers determined the characteristics of the HOPE study population based on age, location and presence of a curable sexually transmitted infection when joining the study. Next, they identified an equal number of women from the placebo group in the ASPIRE trial who had similar characteristics and calculated the HIV incidence in that set. Then the investigators repeated this mathematical sampling of the ASPIRE placebo group 10,000 times. In this modeling exercise, the average HIV incidence was 4.1 new infections per 100 person-years for the ASPIRE participants receiving the placebo -- twice the rate found in the new interim analysis of the HOPE study population. The investigators never calculated an HIV incidence as low as 1.9 per 100 person-years in their mathematical sampling of the ASPIRE placebo group. Comparing the HOPE study population to the ASPIRE placebo group is significantly limited by the differences between the two groups, however. In addition, the HOPE study is not powered to determine the effectiveness of the ring.

The HOPE study is sponsored by the International Partnership for Microbicides (IPM), which developed the dapivirine vaginal ring and is providing it for the study. IPM led a sister study to ASPIRE and is conducting its own open-label follow-on study called DREAM, which also reported interim results today at CROI.

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